Crohn's disease (CD) is a debilitating condition of unknown etiology that is poorly responsive to currently available treatments. Although there is increasing evidence that genetic, immunological, and environmental mechanisms may be involved, the precise cause(s) of this disease remains unclear. Indirect evidence from human studies suggests that CD may be an "autoimmune" disease initiated by a dysregulated immune response against an "unknown" antigen in a genetically susceptible host. One of the difficulties encountered in studying CD has been the lack of appropriate animal models. The unique feature of this proposal is the use a new strain of mice, referred to as SAMP1/Yit. Unlike any other animal model of IBD, these mice spontaneously develop ileitis without genetic or immunologic manipulation. In our colony, virtually 100% of SAMP1/Yit mice develop a severe, chronic transmural ileitis by twenty weeks of age that closely resembles human CD both macroscopically and histologically. The overall objective of the present research proposal is to investigate the key pathogenic mechanism(s) underlying this spontaneous murine model of human CD. The Program Project will be directed by Dr. Fabio Cominelli and will consist of four Projects and three Cores. Project 1, headed by Dr. Fabio Cominelli, will focus on the role of pathogenic and regulatory T cells as well as pivotal Th1 cytokines in mediating chronic intestinal inflammation in this model. Project 2, headed by Dr. Marcia McDuffie, will identify susceptibility genes involved in the predisposition to ileitis in SAMP1/Yit mice. Project 3, headed by Dr. Steven Cohn, will investigate the role of epithelial cells in initiating ileitis in this model. Project 4, headed by Dr. Klaus Key will study the mechanisms of intestinal cell adhesion and inflammatory cell trafficking in SAMP1/Yit mice. These projects will be supported by an Administrative Core which will provide administrative support and coordination. An Animal/Morphology Core will centralize the production and breading of SAMP1/Yit mice with ileitis, provide for centralized pathologic and histologic analysis and generate stocks of genetically modified mice for use in the projects. Lastly, a Cytokine/Immunology Core will provide cytokine analysis as well as T cell transfer and bone marrow chimera experiments for the four projects. The long-term goal of this Program Project is to understand key pathogenic mechanisms of experimental CD in order to begin to develop a cure for this devastating disease.